There is a fundamental gap in understanding molecular interrelationship between longevity and cancer. The long term goal is to understand how a stress-response gene SIRT1 is involved in regulating mammalian longevity and cancer, and to develop novel strategies for cancer treatment and prevention through modulating the gene. The objective of this application is to determine how SIRT1 regulates hematopoietic stem cell functions during aging and upon malignant transformation. The central hypothesis is that SIRT1 is essential for cellular longevity of normal hematopoietic stem cells during aging and under stress, and promotes survival of chronic myelogenous leukemia (CML) stem cells for chemoresistance. The rationale for the proposed research is that better understanding roles of SIRT1 normal and leukemic stem cells will help design an effective strategy to treat CML, and potentially other blood maligancies, by eradicating leukemic stem cells through modulating SIRT1. Thus, the proposed studies is relevant to the NIH's mission to develop fundamental knowledge that will potentially help to reduce the burdens of human disability. Guided by stong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine the role of SIRT1 for normal hematopoietic stem cell functions;2) Determine the role of SIRT1 for CML stem cell survival and chemoresistance;and 3) Determine how SIRT1 regulates mutagenesis in normal and leukemic stem cells. Under aim 1, the consequence of SIRT1 loss on hematopoietic stem cell frequency, quiescence and reconstitution capacity during aging and in response to DNA damage will be determined using bone marrow transplantation assay. Key SIRT1-mediated molecular pathways for stem cell functions will be deciphered. Under aim 2, CML stem cell survival upon inhibition of SIRT1, by gene knockout or small molecule inhibitor, will be determined. Under aim 3, the impact of SIRT1 loss or inhibition on developing genetic mutations in normal hematopoietic stem cells and CML stem cells will be investigated, and key SIRT1-regulated DNA damage repair pathways in stem cells will be identified. The proposed research is significant, because it is expected to shed insight on how SIRT1 plays a role in stem cell aging and tumorigenesis, and to develop a new strategy to eradicate resistant CML stem cells through modulating SIRT1 functions. PUBLIC HEALTH RELEVANCE: This proposal addresses mechanisms of resistance of chronic myelogenous leukemia stem cells to chemotherapy and aging of normal hematopoietic stem cells. The proposed studies have direct relevance to human health as they will shed important insight on how a mammalian stress-responsive gene SIRT1 may regulate cancer and aging. As an important translational outcome of these studies, the combination of SIRT1 inhibitors with BCR-ABL inhibitors may prove a novel therapeutic strategy to eradicate leukemia stem cells and improve treatment of chronic myelogenous leukemia.